Recent research has established that the insulin molecule is capable of inducing T cell proliferation in laboratory animals. The T-cells have immunological specificity and are involved in the cell-mediated immune responses, such as graft responses, response to viral infections, response to neoplasms and so forth. The body's response to antigenic material, such as for example in response to bacterial attack, is the province of antibody secreting cells, called B-cells, which are derived from bone marrow stem cells, but which are not differentiated in the thymus. The antibody response to an antigen, in many cases, requires the presence of appropriate T-cells, so that T-cells are necessary for the body's immune system to make not only cellular immunity responses, but also humoral antibody response.
Current interest in control of the immune response to chemically well-defined natural and synthetic polypeptides has resulted in significant new research discoveries. A particularly interesting finding is that insulin has a profound influence on the overall capacity of an animal to mount a thymus-dependent immune response to the molecule as a whole.
Thus, Snow et al in The Journal of Immunology, volume 124, number 2, pages 739-744, 1980, have demonstrated that the presence of insulin enhanced the Concanavalin A (Con A) reactivity of murine lymphocytes. Once the cells were activated by short-term exposure to Con A, insulin was capable of replacing Con A for the continued stimulation of the cells. This was true both for lymphocyte proliferation and for the generation of nonspecific cytotoxic T lymphoctye. An important aspect of the postulated theory for the proliferative activity observed is the expression of surface insulin receptors on the cells.
Rosenthal et al in Advances in Experimental Medicine and Biology, volume 98, pages 447-458, 1980, have demonstrated that definite regions of the insulin molecule are responsible for the capacity of various subjects, such as mice, guinea pigs and man, to mount a thymus-dependent response to the overall insulin molecule. The thymus-dependent responses comprise activation of T cell function and generation of specific T help and suppression. Rosenthal et al further postulate that the immume response to insulin is genetically determined, with the responsible gene functioning by making an intramolecular selection of discrete regions within the insulin molecule for recognition by the T cell at its insulin receptor site.
Thus, the evidence is strong that the insulin molecule or portions thereof, is capable of affecting the proliferation of T cells as well as affecting T cell subpopulatives, such as T suppressor cells. The T cell subpopulations of suppressor and helper T cells have been implicated in a number of immune response manifestations. Thus, the impairment of suppressor T cell activity is now believed to be a major factor in such autoimmune connective tissue disease as systemic lupus erythematosus. Moreover, in the latter case, as well as in probable impaired immune system responses such as rheumatoid arthritis, it is believed the helper T cells exacerbate the condition.
Also, the theory has been advanced that T suppressor cell hypofunctioning, resulting in inadequate T-B cell cooperation in the immune response, with continuous B cell stimulation and subsequent antibody production may be the cause of the production of antigen-antibody complexes which are the causative agents of renal and inflammatory processes in arthritis and autoimmune diseases.
Thus, it is now apparent that a number of lymphopoietic disorders are undoubtedly associated with abnormalities of T cell and especially suppressor cell function. The loss of suppressor function is at least an early event in certain immune response diseases and is a disease-perpetuating mechanism in others. The loss of suppressor function probably leads to excessive lymphoid cell proliferation and may significantly contribute to lympho-proliferative disorders. The conditions created thereby may be exacerbated by helper T cells.
Compounds capable of inducing T cell proliferation are therefore useful in the therapeutical treatment of various disorders of the immune response.
The present invention relates to short peptide sequences which are synthetic fragment analogs of insulin B chain 8-12 and have been found to exhibit the T cell proliferation inducing properties of the insulin molecule.